HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 42 million people infected worldwide at the end of 2002. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2002, ˜5.0 million new infections were reported, and 3.1 million people died from AIDS. Currently available drugs for the treatment of HIV include nine nucleoside reverse transcriptase (RT) inhibitors or approved single pill combinations(zidovudine or AZT (or Retrovir®), didanosine (or Videx®), stavudine (or Zerit®), lamivudine (or 3TC or Epivir®), zalcitabine (or DDC or Hivid®), abacavir succinate (or Ziagen®), Tenofovir disoproxil fumarate salt (or Viread®), Combivir® (contains −3TC plus AZT), Trizivir® (contains abacavir, lamivudine, and zidovudine); three non-nucleoside reverse transcriptase inhibitors: nevirapine (or Viramune®), delavirdine (or Rescriptor®) and efavirenz (or Sustiva®), and seven peptidomirnetic protease inhibitors or approved formulations: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, and Kaletra® (lopinavir and Ritonavir). Each of these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs have a profound effect on viremia and disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented as a consequence of the widespread application of combination therapy. However, despite these impressive results, 30 to 50% of patients ultimately fail combination drug therapies. Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within certain cell types (e.g. most nucleoside analogs cannot be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when sub-optimal drug concentrations are present. Therefore, novel anti-HIV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options.
Currently marketed HIV-1 drugs are dominated by either nucleoside reverse transcriptase inhibitors or peptidomimetic protease inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recently gained an increasingly important role in the therapy of HIV infections. At least 30 different classes of NNRTI have been described in the literature and several NNRTIs have been evaluated in clinical trials. Dipyridodiazepinone (nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazine derivatives (delavirdine) have been approved for clinical use. However, the major drawback to the development and application of NNRTIs is the propensity for rapid emergence of drug resistant strains, both in tissue cell culture and in treated individuals, particularly those subject to monotherapy. As a consequence, there is considerable interest in the identification of NNRTIs less prone to the development of resistance.
The compounds of this invention inhibit HIV entry by attaching to the exterior viral envelop protein gp120 and interrupting the viral entry process, possibly by interfering with recognition of the cellular receptor CD4. Compounds in this class have been reported to have antiviral activity against a variety of laboratory and clinical strains of HIV-1 and are effective in treating HIV infection (see Hanna et al., Abstract 141 presented at the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, Calif., Feb. 8–11, 2004; Lin et al., Poster 534 presented at the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, Calif., Feb. 8–11, 2004; Hanna et al., Poster 535 presented at the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, Calif., Feb. 8–11, 2004).
N-(3-aryl-3-oxo)acetyl piperidines have been disclosed. See Blair et al., U.S. Pat. No. 6,469,006; Wang et al., U.S. Pat. No. 6,476,034; Wang et al., U.S. Pat. No. 6,632,819; Wallace et al., U.S. Pat. No. 6,573,262 (continuation-in-part application of U.S. Ser. No. 09/888,686, filed Jun. 25, 2001); Wang et al., U.S. patent application Ser. No. 10/214,982 filed Aug. 7, 2002 (continuation-in-part application of U.S. Ser. No. 10/038,306 filed Jan. 2, 2002); Wang et al., patent application WO 03/092695, published Nov. 13, 2003; Wang et al., U.S. patent application US 20040063744, published Apr. 1, 2004. Nothing in these references teaches or suggests the novel compounds of this invention or their use to inhibit HIV infection.